Project Summary: Optic nerve damage is a primary contributor to debilitating vision loss in glaucoma. The prevalence of glaucoma is increasing in the USA and worldwide and there is an urgent need for new, accessible treatments to improve visual outcomes in glaucoma patients. To date, lowering of intraocular pressure (IOP) remains the only treatment strategy with proven efficacy in preserving vision in glaucoma. However, IOP-lowering drugs and surgeries are not effective in all patients, and many patients with seemingly controlled IOP still experience progressive loss of vision. Transforming growth factor-beta (TGF-?) has emerged as playing a key role in progression of optic nerve damage, promoting glial cell activation, extracellular matrix remodeling and, ultimately, formation of glial scar in the optic nerve head (ONH). The overall goal of this application is to provide insight into the effects of blocking angiotensin II type1 receptor (AT1) on glaucoma progression. Our central hypothesis is that AT1 blockade will down-regulate TGF-? expression and pro-fibrotic pathways to ameliorate optic nerve axon loss and glial scarring in glaucoma. In Aim 1: To determine the clinical efficacy of AT1 blocker therapy on the progression of glaucomatous optic neuropathy in vivo, a pre-clinical study will be conducted in a spontaneous glaucoma model. To test the working hypothesis that AT1 blocker therapy will preserve axons and limit scarring in the optic nerve in glaucoma, functional (electrophysiological) and structural (OCT-derived) measures of glaucoma progression in vivo and axon counts in situ will be compared between eyes receiving IOP-lowering therapy alone and in combination with AT1 blocker and untreated eyes, in adult subjects with established glaucoma. In Aim 2: To determine if AT1-blockade affects pathways associated with gliosis and fibrosis in the ONH in this model, gene expression profiling will complement studies that focus on quantifying and localizing mediators of fibrosis in the TGF-? signaling pathway in ONHs in situ in treated subjects relative to untreated controls. These studies will utilize an existing, FDA-approved AT1 blocker with favorable pharmacokinetics, safety profile and unique properties likely to enhance its anti-fibrotic and neuro- protective effects. Significant innovation and strengths of this proposal include the lack of exogenous experimental manipulations to induce glaucoma in a unique, spontaneous model of glaucoma that recapitulates many important features of glaucoma in human patients. The research proposed will enhance mechanistic insight and provide proof of concept that treatment strategies that mitigate the effects of TGF-? signaling limit loss of visual function in spontaneous glaucoma, lending support to a new paradigm for the adjunctive therapy of glaucoma patients.